Sunday, January 29, 2012

Fatigue in Cirrhosis: Is Transplant the Answer?

Clinical Gastroenterology and Hepatology
Volume 10, Issue 2 , Pages 103-105, February 2012
 
Editorial
Fatigue in Cirrhosis: Is Transplant the Answer?
Fatigue is a complex symptom that encompasses a range of complaints including malaise, exhaustion, lethargy, and loss of motivation and social interest. Chronic fatigue is common in the general population, affecting up to 20%.1 Many chronic diseases are associated with fatigue including rheumatoid arthritis, systemic lupus erythematosus,2 and multiple sclerosis.3 Fatigue is often a major factor in the reduction of quality of life associated with chronic disease. Furthermore, the symptom of fatigue does not typically correlate with traditional markers of disease activity, severity, disability, or clinical disease subtype.4, 5 The exact frequency of fatigue in patients with chronic liver disease is variable; however it does constitute the most common complaint.6, 7, 8 Any physician who manages patients with chronic liver disease will acknowledge the presence of fatigue in this patient population. However, because of difficulties in measuring and treating fatigue, it is often minimized.
The study by Kalaitzakis and colleagues9 in this issue of Clinical Gastroenterology and Hepatology follows cirrhotic patients longitudinally pre- and post liver transplantation. As expected, fatigue was greater in patients with cirrhosis as compared with the general population. Additionally, the degree of fatigue was related to the severity of cirrhosis; specifically, patients with higher Child–Pugh classification scores had more severe fatigue.

When discussing fatigue, it is important to differentiate between central and peripheral fatigue.4, 5 Peripheral fatigue, classically manifested by neuromuscular dysfunction and muscle weakness, does not appear to be the main factor in patients with liver disease in the absence of decompensated cirrhosis or liver failure. In comparison, central fatigue is characterized by difficulty performing physical and mental activities: a lack of self-motivation.10 Central fatigue is often associated with an increased perceived effort for tasks.

The prevalence of fatigue varies depending on the specific form of liver disease. Fatigue is well characterized in chronic cholestatic liver diseases including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis.11 In fact, fatigue is present in 50% to 80% of patients with PBC and can often be the presenting symptom.12, 13, 14 Fatigue in PBC has been shown to be a poor prognostic factor, as patients with higher fatigue scores had reduced survival.13 The predominance of fatigue in hepatitic liver pathology is less clearly defined, with chronic hepatitis C,7, 15, 16 autoimmune hepatitis,17 and nonalcoholic fatty liver disease5 the most commonly reported. Additionally, the discussion of fatigue in patients with chronic liver disease must be placed in the context of a diagnosis with an uncertain prognosis and associated social stigma. This patient population also frequently has coexisting psychological issues, including depression and anxiety.18 The presence of hepatic encephalopathy compounds this further. Therefore, the clinical expression of fatigue encompasses complex interactions with biological, psychosocial, and behavioral processes.11 This is supported in the current study where fatigue was highest amongst cirrhotic patients that were unemployed or disabled; again showing the complexity of the clinical picture in this group of patients. Patients with the highest level of fatigue had the lowest described quality of life. Additionally, a significant proportion of patients in the study had anxiety or depression, which dramatically improved post liver transplant.

The pathophysiology of fatigue is complex. Animal models and clinical studies have documented that chronic liver inflammation is associated with changes in the central nervous system (CNS) that manifest as behavioral modifications.19 The inflamed liver communicates with the brain and results in altered brain function. Abnormal central neurotransmission gives rise to behavioral changes in the absence of pathologic CNS tissue damage.20, 21, 22 The neurotransmitters that have been implicated in central fatigue include coricotropin-releasing hormone (CRH),23 serotonin,24 and noradrenaline.25 In fact, pharmacologic targeting of serotonin has proven to be advantageous in managing fatigue in some patients with liver disease.26, 27 In addition to altered neurotransmission, the liver can communicate with the brain via neural, immune cell, or cytokine-driven routes. The liver is innervated by vagal nerve afferents that respond to immune mediators such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and interleukin-6.28, 29 Activated vagal nerves project to different regions of the brain, potentially driving subsequent behavior changes. However, it is likely that this neural pathway plays only a minor role in mediating fatigue in the setting of chronic liver disease because post liver transplant patients (in which the liver is deinnervated) often report little change in their fatigue30; a finding also supported by this current study. Inflammatory mediators and cytokines within the circulation can also interact with their cognate receptors, expressed on the surface of cerebral endothelial cells, to activate their corresponding signaling pathways and subsequently stimulate cells within the brain parenchyma through the release of secondary messengers, including prostaglandins and nitric oxide.31, 32 The CNS is protected by a blood-brain barrier which is impermeable to large, hydrophilic cytokine molecules. However, the circumventricular organs are regions of the brain that lack an intact blood-brain barrier. The fenestrated capillaries allow the passage of inflammatory molecules that can then activate microglia, resident immune cells of the brain.33, 34 Finally, glial cells and neurons within the brain are capable of producing de novo cytokines that can mediate behavior effects, including fatigue.32, 35

The basal ganglia is comprised of 6 nuclei that project to the limbic system and frontal cortex. Fatigue has been linked to alterations in neural activity within the basal ganglia.10 Magnetic resonance imaging (MRI) studies in PBC patients have demonstrated increased signal intensity in the basal ganglia in patients with high fatigue levels.36 A recent study using MRI and voxel-based morphometry, which measures brain tissue density and concentration, found a decrease in brain density in certain areas in patients with cirrhosis.37 The brain areas found to have scores most indicative of decreased brain density were the frontal and parietal regions and putamen for gray matter, and the cingulate gyrus and temporal and frontal regions for white matter. Interestingly, many of these brain areas overlap structurally and/or functionally with the basal ganglia. Intriguingly, post liver transplant patients in this study also had areas of decreased brain density, even several months after transplantation. Cirrhosis had not recurred in these patients, suggesting that neurological injury may be persistent, or at least very slow to improve. The study by Kalaitzakis and colleagues9 is unique as it longitudinally documents fatigue in patients before and after liver transplantation. In concordance with the above-mentioned MRI study, Kalaitzakis et al9 found that fatigue improved post liver transplantation, but only in a minority of patients. The degree of fatigue was still significantly higher than the control population. No specific etiologies of posttransplant fatigue were identified in this study and further work is warranted in this area.

Fatigue in the advanced stages of chronic liver disease is challenging to study due to potential overlap with symptoms associated with hepatic encephalopathy (HE). HE ranges from subtle neuropsychiatric disturbances, only apparent by performing psychometric testing (minimal HE), to varying degrees of confusion, stupor, and coma.38 However, HE is not a requirement for the development of changes within the CNS in patients with chronic inflammatory liver disease. Traditionally, HE was attributed to the toxic effects of ammonia on astroglial cells,39 with hyperammonemia leading to the accumulation of glutamine within astrocytes, causing brain edema due to osmotic stress.40 However, recent attention has focused on the role of systemic inflammation in the development of HE, possibly acting synergistically with ammonia toxicity, including blood-brain cytokine transfer and receptor-mediated cytokine signal transduction.41, 42 These proinflammatory mechanisms are similar in many ways to the pathophysiology underlying behavioral changes and fatigue in the setting of liver inflammation and/or cirrhosis.

Fatigue is a complex and prevalent symptom in patients with chronic liver disease. Several pathophysiological mechanisms for explaining the development of fatigue have been generated; however, our understanding of fatigue in patients with liver disease is still incomplete. Moreover, the issue of fatigue in these patients is even more problematic given the recent findings that liver transplantation often does not completely alleviate this debilitating symptom. Future studies will be imperative to further examine factors predictive of fatigue in post liver transplant patients, and should help to inform us as to potential therapeutic interventions which could be instituted in order to improve fatigue in this clinical setting. Importantly, studies such as that reported by Kalaitzakis et al9 will help us to counsel patients more effectively with regards to expectations post liver transplantation; including that their fatigue potentially may not be significantly improved.
References

Factors Related to Fatigue in Patients With Cirrhosis Before and After Liver Transplantation

Evangelos Kalaitzakis, Axel Josefsson, Maria Castedal, Pia Henfridsson, Maria Bengtsson, Irene Hugosson, Bengt Andersson, Einar Björnsson et al.

Clinical Gastroenterology and Hepatology

Volume 10, Issue 2 , Pages 174-181.e1, February 2012
 
Abstract
Background & Aims We performed a prospective study to evaluate fatigue and identify potential determinants among patients with cirrhosis. We also studied the effects of liver transplantation on fatigue in these patients.

Methods
A total of 108 patients with cirrhosis being evaluated before liver transplantation completed the fatigue impact scale (FIS), the hospital anxiety and depression (HAD) scale, and the short-form 36 (SF-36). Results were compared with controls from the general population. Fasting serum levels of insulin and glucose were measured in all patients. Levels of serum thyrotropin, free T3 and T4, cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year.

Results
Compared with controls, patients with cirrhosis had more pronounced fatigue, on the basis of higher FIS domain and total scores (P < .05), which were related to all SF-36 domains (r = −0.44 to −0.77, P < .001). All FIS scores improved significantly after liver transplantation, although physical fatigue levels remained higher than in controls (P < .05). In multivariate analysis, pretransplant FIS scores were only related to depression, anxiety, cirrhosis severity, and low serum levels of cortisol (P < .05 for all). Impaired renal function and anemia were independent predictors of physical fatigue (P < .05).

Conclusions
Fatigue is common among patients with cirrhosis and associated with impaired quality of life. Psychological distress, severity of cirrhosis, and low levels of cortisol determine general fatigue, whereas anemia and impaired renal function also contribute to physical fatigue. Physical fatigue remains of concern for patients who have received liver transplants for cirrhosis.
 
Discussion Only
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In the current study, we observed high fatigue levels in patients with cirrhosis undergoing pretransplant evaluation. Fatigue was related to impaired HRQL and to being unemployed or having disability pension. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of fatigue in these patients, whereas anemia and impaired renal function are of further importance in physical fatigue. Physical fatigue also appears to be of concern at 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant. Our findings are in line with previously published data showing increased fatigue levels in patients with decompensated cirrhosis compared with those with compensated cirrhosis or liver transplant recipients.39 Fatigue has also been shown to be common in patients with chronic liver disease, but only a fraction of the patients included in these studies had cirrhosis.1, 2, 4, 5, 6 Our study is a systematic evaluation of fatigue in cirrhosis, simultaneously assessing potential associations with psychological distress, hormone abnormalities, and HRQL, as well as the effect of transplantation.
Hypothalamic-pituitary-adrenal dysfunction resulting in hypocortisolism can be accompanied by weakness and fatigue. Hypocortisolism has been reported in patients with chronic fatigue syndrome and fatigued patients with other chronic conditions.12, 13, 25 In cirrhosis, dysfunction of the hypothalamic-pituitary-adrenal axis resulting in hypocortisolism has been previously described,21, 40, 41 and it has been shown to contribute to increased mortality in cirrhotic patients with sepsis.40, 41 Our findings suggest that hypocortisolism might also contribute to fatigue and thus impaired HRQL in cirrhosis.

Psychological distress was found to be a major determinant of fatigue in cirrhosis. It was more closely related to fatigue domains than cirrhosis severity or peripheral factors, such as cirrhosis complications with an impact on patient survival, were. This is in accordance with studies in chronic (liver and nonliver) disease reporting that fatigue correlates strongly with anxiety and depression.1, 5, 6, 12, 13 In our cohort, 23% of patients had significant anxiety or depression as assessed by the HAD, and a dramatic improvement in both fatigue and psychological distress was seen after transplant. Previous studies have questioned the role of depression in the development of fatigue in cholestatic liver disease,3, 42 and antidepressants do not improve cancer-related fatigue.43 Our findings, however, indicate that patients with cirrhosis and significant anxiety or depression confirmed by a psychiatrist might benefit from specific treatment for these disorders, which could lead to improvement in fatigue and HRQL. However, this would need to be formally tested in interventional trials.
Anemia, present in 60% of patients in our cohort, was a predictor of pretransplant physical fatigue. Previous studies have shown that anemia is common in cirrhotic patients and that hemoglobin levels are inversely related to the hepatic venous pressure gradient.44 Interestingly, 35% of patients were found to be anemic after transplant, but this did not affect fatigue. Although anemia in cirrhosis is probably multifactorial, it is conceivable that rigorous measures to treat known anemia causes, especially those related to portal hypertension, could potentially improve fatigue and HRQL.
Fatigue scores were found to be more closely related to Child–Pugh scores compared with the Model for End-Stage Liver Disease (MELD) score. This is in line with previously published data on the closer relationship of the Child–Pugh score with HRQL indexes compared with the MELD score.45 Ascites and hepatic encephalopathy are known to be important factors influencing HRQL in patients with cirrhosis46 and were also found to be associated with fatigue levels in the current study. The fact that the Child–Pugh score but not the MELD score includes ascites and encephalopathy might explain, at least in part, the better correlation with fatigue.

Renal function is often impaired in cirrhosis.16, 18 Although fatigue is common in patients with renal failure and hemodialysis,47 the potential association of renal function impairment with fatigue in patients with cirrhosis has not been previously reported to our knowledge. Renal function has been tested as a potential determinant of HRQL in different cohorts of patients with cirrhosis, but no statistically significant results were obtained.8, 19 However, serum creatinine was used as a measure of renal function in these studies, whereas the GFR assessed by 51 Cr-EDTA clearance was used in the current study.

Although fatigue domain scores improved after transplant, 37% of transplant recipients were physically fatigued 1 year after transplant. Previous studies have shown that physical fatigue is a major problem after liver transplantation,7, 9, 10, 11 but our study specifically assessed fatigue in patients with cirrhosis before and after transplantation in a longitudinal fashion. A discussion about the expected benefit of transplantation on survival is part of the normal pretransplantation consent. Equally, with improving long-term transplantation results, being able to discuss the effect of transplantation on HRQL is central to an informed process. In the current study, almost half of fatigued patients before transplant remained fatigued at 1 year after transplant. However, no distinct potential cause of post-transplant fatigue could be identified. Further studies are clearly warranted on fatigue in transplant recipients.

The main strength of our study is its design, ie, it was a prospective longitudinal study in which validated HRQL instruments were used. Potential determinants of fatigue were carefully characterized, such as 51 Cr-EDTA clearance for GFR assessment, psychometric tests and serum ammonium ion measurements for hepatic encephalopathy, and anthropometry and DEXA measurements for nutritional status. One of the limitations of our study is potential selection bias because patients were recruited from a transplant program. Similarly, patients unable to fill in questionnaires were excluded, which might have underestimated the impact of more severe grades of hepatic encephalopathy on fatigue. Also, serum total cortisol measurements, used in the current study, are thought to overstate adrenal insufficiency in cirrhosis.21 However, hypoalbuminemia (<25 g/L) is the only reported risk factor for misdiagnosis of adrenal insufficiency by serum total cortisol assays.21 In the present study, only 1 patient with low serum cortisol had albumin <25 g/L, and exclusion of this patient from the analysis did not alter our results. Ideally, however, future studies investigating the role of glucocorticoids on fatigue in cirrhosis should use salivary cortisol measurements (not affected by hypoalbuminemia21) and synachten testing to identify patients with altered cortisol response.40, 41 Finally, controls were only asked to complete the FIS and not the questionnaire related to psychological distress (HAD), and they did not undergo any blood tests. In an attempt to improve the response rate of controls, published data on HAD results from the general Swedish population34 and established cutoff values of the laboratory of our institution38 were used.
In conclusion, patients with cirrhosis show increased fatigue, which impairs HRQL. Anxiety and depression as well as cirrhosis severity and hypocortisolism seem to be important determinants of most fatigue domains, whereas anemia and impaired renal function are of further importance in physical fatigue. Liver transplantation was associated with improvement in fatigue, but physical fatigue appeared to be of concern 1 year after transplant, with almost half of physically fatigued patients remaining fatigued after transplant.

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Saturday, January 28, 2012

The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis

Journal of Hepatology
Article in Press

The phenotypic fate and functional role for bone marrow-derived stem cells in liver fibrosis

Tatiana Kisseleva
Affiliations
Corresponding author. Address: 9500 Gilman Drive # 0702, La Jolla, CA 92093, USA. Tel.: +1 858 822 5339., David A. Brenner Dept. of Medicine, University of California, San Diego, CA, USA

Received 5 April 2011; received in revised form 12 August 2011; accepted 4 September 2011. published online 14 December 2011.

Corrected Proof


Summary
Liver fibrosis is an outcome of chronic liver injury of any etiology. It is manifested by extensive deposition of extracellular matrix (ECM) proteins that produce a fibrous scar in the injured liver. Bone marrow (BM) cells may play an important role in pathogenesis and resolution of liver fibrosis. BM cells contribute to the inflammatory response by TGF-β1 secretion and activation of liver resident myofibroblasts. Moreover, BM itself can serve as a source of collagen expressing cells, e.g. BM-derived fibrocytes and mesenchymal progenitors, which in turn, have a potential to in situ differentiate into fibrogenic myofibroblasts and facilitate fibrosis. Finally, BM cells play an active part in resolution of liver fibrosis after cessation of fibrogenic stimuli. While natural killer (NK) cells are implicated in apoptosis of activated hepatic stellate cells/myofibroblasts, cells of myelo-monocitic lineage secrete matrix metalloproteinases to actively degrade the fibrous scar. The focus of this review is on the current understanding of the role of different subsets of BM cells in the onset, development and resolution of liver fibrosis.

Introduction 
Liver fibrosis is caused by chronic injury which triggers apoptosis of hepatocytes, damage of the endothelial barrier, recruitment of inflammatory cells, increased secretion of TGF-β1, and activation of myofibroblasts responsible for scar formation [10], [50]. However, the contribution of bone marrow (BM) cells to liver fibrosis remains controversial [44], [51]. At the onset of fibrosis, BM cells are recruited to the site of injury to facilitate inflammation. It is believed that monocytes and macrophages are the primary source of TGF-β1, the major fibrogenic cytokine that plays a critical role in activation of fibrogenic myofibroblasts.

Myofibroblasts express type I collagen and other extracellular matrix proteins that constitute the fibrous scar in liver fibrosis. Three sources of myofibroblasts have been identified: hepatic stellate cells (HSCs) in hepatotoxic liver injury [27], portal fibroblasts in cholestatic liver injury [18], and fibrocytes in any inflamed liver (Fig. 1). Most myofibroblasts retain the markers of being originally derived from either fibroblasts (such as Thy1 and elastin), HSCs (such as vitamin A droplets, GFAP, and desmin), or fibrocytes (CD45). Theoretically, myofibroblasts may also be derived directly from a precursor cell, unrelated to stellate cells, fibroblasts, or fibrocytes. Cell fate mapping studies in reporter mice have demonstrated that both hepatic stellate cells and fibroblasts are septum transversum mesenchymal cells that migrate from the mesothelium and submesothelium C [5].



  • Figure 1


    Possible origins of fibrogenic myofibroblasts.
    Hepatic myofibroblasts may originate from liver resident mesenchymal cells. These include hepatic stellate cells, which under physiological conditions reside in the space of Disse in a quiescent state, and in response to injury undergo activation into myofibroblasts. Portal fibroblasts may also be a source of myofibroblasts in the fibrotic liver. In addition, BM-derived hematopoietic and mesenchymal cells may contribute to the myofibroblast population. While the role of mesenchymal stem cells in liver fibrosis is not well characterized due to the lack of specific markers and difficulties with their isolation, hematopoietic stem cells contribute to hepatic fibrocytes in response to liver injury.
Cessation of the injury often causes resolution of liver fibrosis with resorption of the fibrous scar [40], [41]. Under these circumstances, activated myofibroblasts undergo senescence [53], [77], [80], apoptosis and disappear [42], [73]. It has been shown that NK (and NKT) cells facilitate aHSCs apoptosis during regression of fibrosis [72], while newly recruited monocytes actively degrade extracellular matrix proteins (ECM) [20] via upregulation and secretion of matrix metalloproteinases (e.g. MMP13) [95] and collagenases [43].

Stem cell biology has become one of the most intensely studied areas of biomedical research and there is great optimism among scientists and the lay public that stem cells will be used as novel therapies for many incurable chronic diseases. Many institutions, including the State of California, have committed billions of dollars specifically to promote stem cell research with the goal of developing new therapies within a few years. As a result of new insights into stem cells, there is a renewed interest in the role of the bone marrow and its stem cells in liver fibrosis. The information to date is very conflicted, with different studies showing either a contributing effect or a therapeutic effect of bone marrow-derived cells to liver fibrosis.

Many studies have raised the issue of whether liver myofibroblasts may be derived from bone marrow stem cells, either hematopoietic or mesenchymal stem cells. Due to their well defined cell lineage markers and methodology for hematopoietic stem cell transfer, the contribution of hematopoietic stem cells to the population of liver myofibroblasts may be readily assessed in experimental murine liver fibrosis.

This review will address three issues: (1) the role of BM-derived macrophage to liver fibrogenesis, (2) the contribution of BM cells to myofibroblasts in the fibrotic liver, and (3) the role of BM stem cells in the resolution of liver fibrosis.

Inflammation
Expression of collagen type I marks fibrogenic/hematopoietic cells

While the fibrogenic properties of fibrocytes will be discussed below, it is important to note that expression of collagen type I by hematopoietic cells has a critical role in the development and maturation of hematopoietic BM cells required to mediate injury-triggered immune responses [22], [78], [89]. First, activated macrophages upregulate collagen type I upon maturation and migration to the site of injury [67]. Surprisingly, the level of collagen expression in activated macrophages is similar to activated cultured fibrocytes or fibrocyte-like cells [67]. Second, upregulation of collagen type I is associated with maturation of hematopoietic stem cells [22], [78], [89]. It is unknown why collagen expression is required for the function of hematopoietic stem cells. A recent study suggested that collagen I regulates the self-renewal of mouse embryonic stem cells through α2β1 integrin- and DDR1-dependent Bmi-1 [89]. However, the level of collagen expression in activated macrophages and fibrocytes is relatively low compared to activated myofibroblasts [67], [79], so that these cells are not major sources of collagen, but most likely mediate cellular interaction [78] with extracellular matrix causing cytoskeletal rearrangement [17], [31], [86].




Increased intestinal permeability has a critical role in the pathogenesis of liver fibrosis [81], [104]. Recent studies have demonstrated that in addition to phagocytosis, neutrophils, macrophages, and fibrocytes may utilize an alternative pathway to combat bacteria, by releasing extracellular DNA-based traps enriched in histones and major antimicrobial enzymes, cathelescidin and myeoloperoxidase [12], [16], [97], [106]. It remains unclear why terminally differentiated cells with phagocytic capacity decide to intake or exterminate bacteria [16]. This mechanism is activated in Vegenar granulomatosus [46] and Lupus nephritis [34]. Although the significance of such phenomenon for liver fibrosis still has to be investigated, fibrocyte-like cells from the spleen (CD45+Collagen-α1(I)+ BM-derived cells) may form DNA traps following LPS- or CCl4-induced liver injury [52]. Thus, identification and classification of fibrocytes and fibrocyte-like cells recruited to the injured liver may provide new insights into the pathogenesis of liver fibrosis.

Recruited BM macrophages induce fibrosis
BM macrophages and Kupffer cells (liver resident macrophages) are the major source of TGF-β1 in liver fibrosis [81]. T and B lymphocytes are also recruited to the site of injury and further facilitate secretion of fibrogenic cytokines. Ablation of myolo-monocytic CD11b+ cells in mice at the onset of liver fibrosis attenuated activation of fibrogenic myofibroblasts and collagen deposition in liver and kidney fibrosis [20], [21], [45].

Bacterial flora and toll-like receptor (TLRs) signaling are critical in the activation of Kupffer cells/macrophages and TGF-β1 release [81]. For example, TLR4 mutant and knockout mice are resistant to fibrosis of different etiologies [38]. Moreover, genome wide analysis studies have demonstrated that individuals carrying a low efficiency polymorphism in TLR4 gene are less susceptible to HCV-induced liver fibrosis [56]. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMP) such as lipopolysaccharide (LPS), bacterial cell wall component, peptideglycan, and bacteria-derived unmethylated CpG-DNA [38]. In addition, endogenous ligands (alarmins, e.g. HMGB-1, hyaluronan) can bind TLR4 in the presence of CD14 and LPS-binding protein [LBP) and transduce similar signals [105]. Upon activation of TLRs, recruited BM cells produce inflammatory cytokines, such as TNF-a, IL-6, IL-1, MCP-1, and RANTES [82]. Moreover, microbial products have a significant impact on fibrogenic progression [104], and LPS synergistically facilitates other fibrogenic factors such as TGFβ-1, oxidative stress, and mechanical injury [2]. TLR4 on BM cells is important in experimental alcoholic liver disease [39], and TL9 on BM cells is important in experimental non-alcoholic steatohepatitis [61].

Antifibrotic effects of macrophages 
Original experiments by Duffield et al. [20] and subsequent studies [60], [102] have demonstrated that, over a period of time, two functionally distinct types of macrophages are recruited to the injured liver. During the injury phase, pro-fibrogenic macrophages mediate recruitment of injury-associated macrophages that promote myofibroblast proliferation and apoptosis [32]. In contrast, during recovery from injury, a population of macrophages predominates that resembles classical macrophages and does not promote HSC survival but mediates matrix degradation. This macrophage population is present during resolution of injury and at a time when pro-fibrogenic and inflammatory mediator levels are decreasing [20]. These two functional phenotypes are separated chronologically in experimental liver fibrosis by several days, suggesting that they may represent different populations.
How do monocytes/macrophages promote matrix degradation? First of all, during the resolution phase, myelo-monocytic cells serve as a source of collagen degrading enzymes, such as collagenase and other matrix metalloproteinases (MMPs) [24], [36], [99]. Thus, increased secretion of MMP13 by hepatic macrophages is critical for dissolution of the fibrous scar in the recovering liver [24]. In addition, macrophages are responsible for clearance of apoptotic cells [10], [58], [69].

 

Fibrogenic myofibroblasts
Definition of myofibroblasts Myofibroblasts are characterized phenotypically by a stellate shape and expression of stress fibers, abundant pericellular matrix and fibrotic proteins (α-smooth muscle actin (α-SMA), non-muscle myosin, fibronectin, vimentin, and collagen type I) [23]. Ultrastructurally, myofibroblasts are defined by prominent rough endoplasmic reticulum (rER), a Golgi apparatus producing collagen, peripheral myofilaments, fibronexus (no lamina) and gap junctions [23]. Myofibroblasts are implicated in wound healing and fibroproliferative disorders [28], [57]. Myofibroblasts are produced in response to fibrogenic stimuli, such as TGF-β1 [65]. Classic myofibroblasts differentiate from a mesenchymal lineage and, therefore, lack expression of lymphoid markers such as CD45 or CD34. However, subsets of myofibroblasts can express Thy1.1 (CD90) or CD34. It remains unclear whether expression of these genes links (myo)fibroblasts to hematopoietic stem cells, or these antigens have a broader distribution than previously appreciated. Sustained injury may trigger (trans)differentiation of myofibroblasts from other cellular sources, including HSCs [10].
The question remains whether BM-derived cells are capable of giving rise to the functional myofibroblasts in liver fibrosis. Several BM cells have been implicated in fibrogenesis, such as fibrocytes and circulating mesenchymal cells, which could contribute to liver fibrosis.

 

The origin of fibrogenic myofibroblasts 
Although initial reports have suggested that BM may be a source of fibrogenic myofibroblasts [26], [75], most recent studies have reported that the majority of myofibroblasts activated in response to injury are from liver resident cells [37], [48], [49], [51], [81]. These findings are based on BM transplantation techniques in mice, in which the collagen-α1(I) or collagen-α2(I) promoters drive expression of the GFP reporter only in BM cells [37], [51]. Since collagen-α1(I) or collagen-α2(I) fibers are expressed in the same cells to form a triple helix [85], these reporter genes are expected to exhibit identical localization. Indeed, similar results were obtained in both mice in response to two models of liver fibrosis [37], [51], bile duct ligation and toxic liver injury induced by CCl4, demonstrating that activated myofibroblasts do not originate in the BM but emerge from the liver resident cells, e.g. HSCs and portal fibroblasts. Meanwhile, a small population of collagen type I expressing BM-derived cells, scattered in the liver and spleen of these mice, is composed of fibrocytes [37], [51]. Despite differences in experimental approaches and duration of injury, there was no evidence that BM contributes to replenishment of HSCs and portal fibroblasts or liver stem cells.

Fibrocytes are implicated in fibrogenesis of parenchymal organs 
Fibrocytes are defined as spindle shaped “CD45 and collagen type I (Col+) expressing leukocytes that mediate tissue repair and are capable of antigen presentation to naive T cells” [13]. Due to their ability to differentiate into myofibroblasts, fibrocytes are implicated in the fibrogenesis of skin, lungs, kidneys, and the liver [1], [48], [87]. In addition to collagen type I, fibronectin and vimentin, fibrocytes express CD45, CD34, MHCII, MHCI, CD11b, Gr-1, and secrete growth factors (TGF-β1, MCP-1) that promote deposition of ECM [11], [70]. Upon injury or stress, fibrocytes proliferate in the BM and migrate to the injured organ [13], [70]. The reported number of recruited fibrocytes varies from 25% (lung fibrosis) [48], [88] to ∼3–5% (liver fibrosis, e.g. BDL and CCl4) [49] of the collagen expressing cells, suggesting that the magnitude of fibrocyte differentiation into myofibroblasts depends on the organ and the type of injury. Fibrocytes originate from hematopoietic cells and differentiate in the liver into typical myofibroblasts [79]. Mice treated with human serum amyloid protein (hSAP) [66], a natural inhibitor of fibrocyte differentiation and maturation, develop less fibrosis in response to injury. Our data and studies in other parenchymal organs [14], [63], [68] clearly demonstrate that fibrocytes play an important role in pathogenesis of many fibrogenic disorders, including lungs. Elevated levels of circulating fibrocytes in peripheral blood in patients with lung fibrosis have a poor prognostic value [62]. Moreover, hSAP has been successfully tested in limited clinical trials in patients with skin, kidney and lung fibrosis [14], [59], [63], [68].

BM mesenchymal stem cells (MSCs) 
MSCs are defined as self-renewable, multipotent progenitor cells with the capacity to differentiate into lineage specific cells that form bone, cartilage, fat, tendon and muscle tissue [44], [84]. Unlike hematopoietic stem cells, MSCs are radio- and chemoresistant [9] and do not express progenitor markers (CD45, CD34, 133 [44]) or myelo-monocytic markers (CD11b, MHCII, and F4/80). Hepatic myofibroblasts may arise from BM-derived mesenchymal progenitors [26], [75]. BM-derived mesenchymal progenitors can give rise to myofibroblasts in the injured liver [6], [19], [55]. BM-derived cells may populate fibrotic lungs [35] and the liver [75] and contribute to fibrosis by differentiating into tissue myofibroblasts [40], [48], [75]. By subfractionating the BM stem cell compartment, the hepatic BM-derived myofibroblast-like cells were reported to be of mesenchymal stem cell origin [44], [75]. Cultured mesenchymal stem cells have the potential to become myofibroblast-like cells when transplanted into mouse livers [6], [19].

Whether circulating mesenchymal progenitors significantly contribute to ECM deposition in the course of experimental liver fibrosis remains to be determined, but they most likely represent a population, distinct from hematopoietic-derived fibrocytes [51]. Unlike hematopoietic stem cells, the definitive markers for mesenchymal stem cells have not been identified, and ablative radiation protocols to establish donor cell transfer have not been standardized. Therefore, a definitive murine liver fibrosis experiment with documented transfer of all bone marrow constituents expressing a myofibroblast specific marker has not been reported. Although initial enthusiasm about the BM origin of myofibroblasts declined in the recent years, further studies are required to re-evaluate this phenomenon.

Liver fibrosis precedes development of hepatocellular carcinoma [10], [38]. Recruitment of BM-derived fibroblasts (including fibrocytes) has been implicated in the pathogenesis of liver cancer, and cancer of other organs [8]. Thus, using collagen-α1(I)-GFP and α-smooth muscle actin (SMA)-RFP mice, BM-derived myofibroblasts were shown to contribute to neoplasia in gut and intestine [71]. Since most liver injury models in mice develop within a short period of time, it is possible that these experimental conditions are too short for the recruitment of BM myofibroblasts, as seen in cancer during 8–9months of development.

Contribution of BM cells in genetically altered mice 
BM cells may have different roles in different mouse models of genetically-induced liver injury. Since these phenomena are usually not observed in the wild type mice, contribution of BM-derived cells to hepatic cells is discussed separately.

The classical example is FAH−/− mice, in which a mutation in fumaryl-aceto-acetate hydrolase (FAH) gene causes a metabolic disorder equivalent to hereditary tyrosinemia type 1. Withdrawal of the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) from drinking water causes extensive apoptosis of FAH−/− hepatocytes in these mice. Transplantation of wild type BM into these mice results in rescue from fatal liver failure by FAH-deficient hepatocytes. Wild type BM myelo-monocytes cells fuse with damaged hepatocytes to give rise to colonies of functional hepatocytes [54], [98]. Moreover, infusion of myeloid cells alone is sufficient to give rise to functional hepatocytes [3], [92], [101]. However, fusion of hepatocytes with macrophages was only rarely observed in wild type mice in response to other types of liver injury (CCl4, BDL), suggesting that hematopoietic cells have a limited contribution to hepatocyte population under physiological conditions or in response to injury [3], [92].

Recruitment of fibrocytes into the injured liver representing a high percentage of myofibroblasts has been observed in Abcb4-deficient mice (Abcb4−/− mice), and has been shown to substantially ameliorate development of liver fibrosis [74]. However, only a modest contribution of fibrocytes to liver fibrosis (3–5% of fibrogenic myofibroblasts) has been observed in wild type mice in response to CCl4 and BDL [51], [79]. Although Abcb4-deficient mice provide a unique opportunity to study recruitment of fibrocytes in great detail, they do not reflect the fibrocyte contribution to the population of myofibroblasts in hepatotoxic or cholestatic injury.

Resolution of liver fibrosis
Disappearance of myofibroblasts Reversal of fibrosis is associated with increased collagenase activity, activation of macrophages/Kupffer cells that secrete matrix metalloproteinases, e.g. MMP-13, and matrix degradation [24], [95]. Senescence and apoptosis of activated HSCs play a significant role in resolution of liver fibrosis by eliminating the cell type responsible for producing the fibrotic scar [41], [53]. Several mechanisms are implicated in the apoptosis of activated HSC: (1) activation of death receptor-mediated pathways (Fas or TNFR-1 receptors) and caspases 8 and 3; (2) upregulation of pro-apoptotic proteins (e.g., p53, Bax, caspase 9); and (3) decrease of pro-survival genes (e.g., Bcl-2) [50]. A population of liver-associated natural killer (NK) cells and NKT cells mediate apoptosis of activated HSCs [72]. Kupffer cells and BM macrophages actively participate in clearance of apoptotic cells and degradation of extracellular matrix proteins.

Studies in culture suggest that aHSCs, at least in part, can revert to a quiescent phenotype. Therefore, the disappearance of activated α-SMA+ Col+ HSCs in the course of fibrosis reversal may indicate that activated HSCs return to their quiescent state, which is associated with expression of lipogenic genes (Adfp, Adipor1, CREBP, PPAR-γ) [83] and storage of vitamin A in lipid droplets. Depletion of peroxisome proliferator-activated receptor gamma (PPAR-γ) constitutes a key molecular event for HSC activation, and ectopic over-expression of this nuclear receptor results in the phenotypic reversal of activated HSC to quiescent cells in culture [83]. The treatment of activated HSCs with an adipocyte differentiation cocktail, over-expression of SREBP-1c, or culturing on basement membrane-like ECM [29], [100] result in up-regulation of adipogenic transcription factors and cause morphologic and biochemical reversal of activated HSCs to quiescent cells [93], [94]. Although these results suggest that activated HSCs can revert to a quiescent state, these findings have only been documented in cultured cells.

Therapy
Many studies have demonstrated that transplantation of bone marrow cells reduces experimental liver fibrosis ([76], [90] and others). The mechanism is not trans-differentiation of bone marrow cells into hepatocytes. More likely, hematological stem cells may contribute to the reversal of liver fibrosis via macrophages that produce collagenases [91] and phagocytose dead parenchymal cells [69]. More unexpectedly, mesenchymal stem cells, even though they have the potential to become myofibroblasts, also have functions that may contribute to the reversal of fibrosis. Cultured mesenchymal stem cells secrete agonists that inhibit hepatocyte apoptosis, induce hepatocyte proliferation, and increase hepatocyte specific gene expression [96]. Also, mesenchymal stem cells may be induced in culture to become endothelial progenitor cells (EPCs). Transplantation of EPCs reverses hepatic fibrosis and improves survival in CCl4-induced cirrhosis in rats [64].

BM cells for anti-fibrotic therapy 
The improvement of liver function following transplantation of hematopoietic progenitors in mice and rats with injured livers provided the basis for clinical trials [25]. Clinical studies with adoptive transfer of autologous CD133+ BM cells in patients have been reported to stimulate liver regeneration [4]. Similar to that, autologous infusion of CD34+ blood cells, or even monocytes, improved biochemical parameters and stimulated liver regeneration [33]. Within the limits of these small, uncontrolled clinical trials, evidence is starting to accumulate that transplantation of hematopoietic progenitors may be beneficial in patients. However, the mechanism of their action remains to be defined. Such improvement may result from release of cytokines and growth factors by transplanted hematopoietic cells, or occur due to infusion of scar-resorbing monocytes. In concordance with these observations, treatment with granulocyte-colony stimulating factor (G-CSF) was used to mobilize the BM cells and demonstrated a positive histological effect in patients with alcoholic steatohepatitis [30].
Mesenchymal stem cells serve as another potential target for the liver stem cell therapy. In addition, mesenchymal cells are readily available (for example, from fat tissue) and relatively easy to expand in vitro. A recent study investigated the ability of purified hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and mononuclear cells to engraft and contribute to liver regeneration in response to injury in mice [15]. However, only a low level of engraftment with the MSCs and reconstitution of the liver mass has been reported [7].

In concordance with this notion, injection of MSC-derived conditioning media into a liver-assist device decreased hepatocyte apoptosis and increased their proliferation [96], [103]. However, recent studies have raised a safety question on MSCs transplantation, demonstrating that MSCs can give rise to myofibroblasts in mice in response to liver injury. For example, BM-derived MSCs contributed to the development of liver fibrosis in chimeric mice that received bone marrow transplantation with an enriched BM mesenchymal fraction, and subjected to the CCl4-liver injury [75]. Taken together, both hematopoietic and mesenchymal stem cells demonstrate a limited, if any, contribution to hepatocyte replenishment, but may stimulate liver function by providing soluble growth factors or cytokines [3], [49], [92].
A few clinical trials have been performed in patients with end-stage liver disease caused by hepatitis B, hepatitis C, alcoholic liver disease, and cryptogenic fibrosis. These patients were transplanted with autologous MSCs harvested from the iliac crest. The tested parameters (albumin, creatinine) demonstrated a modest but significant improvement without severe adverse effects, suggesting that MSCs might be useful for the treatment of end-stage liver disease with satisfactory tolerability [47].

Conclusions 
The literature provides evidence that bone marrow cells might contribute to increase or to inhibit experimental liver fibrosis  Figure 2. Although there is clearly a need for additional, better defined studies, some conclusions can be made from our current information. Hematological stem cells are the source of monocytes, Kupffer cells and recruited macrophage. Overall, these cells contribute to the initial inflammation in the injured liver that progresses to liver fibrosis. However, recruited macrophages may also secrete agonists such as IL-10 that inhibit stellate cell activation as well as collagenases that cause regression of fibrosis. Hematological stem cells are also the source of fibrocytes, which are recruited to the injured liver and function in the innate immune response as well as differentiate into myofibroblasts. Mesenchymal stem cells have the capacity to become myofibroblasts, but studies to follow their cell fate in vivo are limited by the lack of specific markers.


  • Figure 2
    Potential roles of BM-derived progenitor populations in liver injury. BM is the source of hematopoietic and mesenchymal stem cells, which may participate in the response to liver injury.
Most, but not all, studies using BM transplantation have demonstrated a beneficial effect on experimental liver fibrosis. The mechanism for this benefit is unclear, and in particular BM-derived cells do not constitute a significant source of hepatocytes in the injured liver. However, both mesenchymal stem cells and hematopoietic stem cells are reported to contribute to the regression of liver fibrosis. On the basis of these studies, small, mostly uncontrolled clinical studies have treated cirrhotic patients with autologous transplantation of BM derived cells. Although these studies have established the feasibility of this approach, the mechanism and long term benefit of transplantation of BM-derived cells in cirrhosis is unknown.

Conflict of interest
The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The underlying research reported in the study was funded by the NIH Institutes of Health.

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